Bronchoscopy as an indicator of tracheobronchial fungal infection in non-neutropenic intensive-care unit patients

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1 ORIGINAL ARTICLE INFECTIOUS DISEASES Bronchoscopy as an indicator of tracheobronchial fungal infection in non-neutropenic intensive-care unit patients O. Yazıcıoglu Moçin 1, Z. Karakurt 1, F. Aksoy 2,G.G ung or 1, M. Partal 3,N.Adıg uzel 1, E. Acart urk 1, S. Batı Kutlu 4, R. Baran 5 and H. Erdem 6 1) Pulmonology and Respiratory Intensive Care Unit, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 2) Department of Pathology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 3) Department of Microbiology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 4) Department of Infectious Diseases and Clinical Microbiology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 5) Department of pulmonology, Acibadem Fulya Hospital, Istanbul, Turkey and 6) Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul, Turkey Abstract We aimed to establish that a bronchoscopic view can be as reliable as microbiology, and support an empirical tracheobronchial fungal infection (TBFI) treatment decision. We retrospectively studied 95 respiratory failure patients with suspected TBFI admitted to the intensive-care unit (ICU) in 2008 with sticky secretions, hyperaemic mucosa, and whitish plaques on bronchoscopic view. Patients not suspected of having TBFI were chosen as a control group (n = 151). Broncheoalveolar lavage (BAL) fluid was cultured, and biopsy samples were taken from the lesions. Biopsy samples positive for fungi were defined as proven, only BAL-positive (+ fungi) cases were probable TBFI, and BAL-negative ( fungi) cases were possible TBFI. BAL (+ fungi) and BAL ( fungi) in the control group were defined as colonization and no TBFI, respectively. The sensitivity, specificity and positive and negative predictive values of BAL (+ fungi) were 85.1% (63/74), 81.4% (140/172), 66.3% (63/95), and 92.7% (140/151), respectively. Biopsies were performed in 78 of 95 patients, and 28 were proven TBFI with fungal elements, and 100% were BAL (+ fungi). Probable TBFI was seen in 30 of 95 patients with BAL (+ fungi), and possible TBFI (BAL( fungi)) in 25 of 95. Among the 95 patients, microbiology revealed fungi (90.5% Candida species; 9.5% Aspergillus) in63 (66.3%). In the controls, the colonization and no TBFI rates were 11 of 151 and 140 of 151, respectively. Observing sticky secretions, hyperaemic mucosa and whitish plaques by bronchoscopy is faster than and may be as reliable as microbiology for diagnosing TBFI. These findings are relevant for empirical antifungal therapy in suspected TBFI patients in the ICU. Keywords: Bronchoscopy, fungal infection, intensive-care unit, respiratory failure Original Submission: 3 February 2012; Revised Submission: 26 September 2012; Accepted: 14 November 2012 Editor: E. Roilides Article published online: 22 November 2012 Clin Microbiol Infect 2013; 19: E136 E / Corresponding author: H. Erdem, Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul, Turkey hakanerdem1969@yahoo.com Introduction Flexible bronchoscopy (FB) is an extremely crucial method in the intensive-care unit (ICU) and an important diagnostic tool for the pulmonologist [1,2]. Endobronchial lesions can be observed and diagnostic specimens, lavage and brush materials can be easily obtained by FB [3]. Accordingly, FB has a considerable place in the management of tracheobronchial fungal infections (TBFIs). However, the diagnosis of TBFI by microbiology and pathology analysis takes 2 3 days at a minimum. Combined with the high rate of colonization [4], this means that, particularly in mechanically ventilated patients [5], a rational therapeutic approach may be delayed or obscured. Only a few studies have documented fungal disease in critically ill, non-neutropenic patients [4,6,7]. To Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases

2 CMI Yazıcıoglu Mocßin et al. Bronchoscopy as an indicator of TBFI E137 the best of our knowledge, no one has yet assessed the value of the bronchoscopic inspection in TBFIs to provide clues for rational antifungal treatment. In our respiratory ICU, patients in whom we observed sticky secretions accompanied by hyperaemic and irregular mucosa, followed by whitish plaques and subsequent nodules, were frequently confirmed by microbiology and histopathology to have TBFI. It is already known that fungal disease may manifest as mucosal plaques in infants, older adults who wear dentures, patients being treated with antibiotics, chemotherapy, or radiation therapy, and those with cellular immunodeficiency [8 11]. Recently, bronchoscopy TBFI findings in immunocompromised patients were summarized in a review [12]. We hypothesized that patients with these bronchoscopic findings could alert us to suspect TBFI in critically ill patients in the ICU. In this study, which is the first and the largest of its kind, we evaluated the detection of whitish plaques by bronchoscopic examination of the tracheobronchial tree, relative to the clinical and laboratory data, in non-neutropenic ICU patients with acute respiratory failure (ARF), to provide evidence for empirical antifungal treatment. Materials and Methods This retrospective, observational, case control study was conducted in the respiratory ICU of Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey. Our unit is labelled as a level III ICU, and has a 20-bed capacity. The criterion for inclusion of patients in the study was clinical suspicion of TBFI [12] during FB in a patient with ARF [13]. The study was carried out between 1 January and 31 December All invasive procedures, including FB, were performed as a result of clinical indications, and all patients provided signed informed consent. We obtained hospital approval from the Institutional Review Board for this study. FB (Olympus) FB was performed for aspiration of secretions and for diagnostic analyses in eligible intubated patients. The nasal route was used for observing the upper level of the vocal cords in all non-intubated patients. The bronchoscopic view for suspected TBFI TBFI was suspected when whitish, sticky secretions, oedematous hyperaemic mucosa and/or mucosal plaque formation were observed. When TBFI was suspected, a bronchial mucosal biopsy was performed in all eligible cases. Modified definitions of TBFI We prepared a flow chart (Fig. 1) for definitions of proven, probable and possible TBFIs, and colonization or no TBFI, with the aid of guidelines [5]. Proven TBFI: in the case of suspected TBFI, tissue biopsy and tracheobronchial washing reveal fungi. Probable TBFI: in the case of suspected TBFI, the pathology findings are negative, but the microbiology results of tracheobronchial washing reveal fungi. Possible TBFI: TBFI is suspected, but pathology and microbiology findings are negative for fungi. Colonization: tracheobronchial washing reveals fungi without bronchoscopic suspicion of TBFI. No TBFI: patients have no bronchoscopic findings of TBFI, and have negative histology or microbiology findings for fungi. Data collection Patient demographics, APACHE II scores [14] on admission to the ICU, reasons for ARF [13], pneumonia [1,2], chronic obstructive pulmonary disease exacerbation, infections following thoracic surgery, chronic parenchymal diseases, pre-icu locations, mechanical ventilation, day of bronchoscopic sampling, length of pre-icu stay, tracheostomy, diabetes mellitus, steroid use, tracheal complications and laboratory data were recorded. Pathology Biopsy samples were examined after staining with Grocot and periodic acid Schiff reagent. TBFI was characterized by disintegration of the surface epithelium, acute inflammatory cell infiltration and fibrin in the bronchial and tracheal mucosa, and yeast-like pseudohyphae among the necrotic cells [15,16]. The type of fungus was not determined. Patients were further separated into two groups according to whether the histopathology findings were positive or negative for fungi. Microbiology Bronchial and tracheal washings were cultured onto Sabouraud s dextrose agar, and a microbiological culture analyser (mini API; Biomerieux, Marcy l Etoile, France) was used for mould and yeast identification. Candida was classified into albicans and non-albicans; further differentiation of Candida could not be performed, owing to inadequate laboratory resources. Aspergillus was identified by inoculating bronchial and tracheal washings onto Sabouraud s dextrose agar; colonies that were fast-growing and white, yellow, yellow brown, brown to black or green in colour were accepted as positive. Bacterial cultures were quantified and microorganisms with >10 4 CFUs/mL were assessed as indicative of an infection requiring bronchial washing. Urine, blood, tracheal aspirate and other examples were also examined when needed.

3 E138 Clinical Microbiology and Infection, Volume 19 Number 3, March 2013 CMI Bronchoscopy findings such as: Whitish, sticky secretions, oedematous hyperaemic mucosa, and/or mucosal plaque formation on vocal cord, epiglottis and upper or lower part of tracheal mucosa No TBFI Absent Present Suspected TBFI Pathology for fungi Negative Positive Fungi present Fungi absent Positive for fungi Negative for fungi Colonization No TBFI FIG.1. Flow chart of suspected Proven TBFI Probable TBFI Possible TBFI tracheobronchial fungal infection (TBFI) by bronchoscopy. Antifungal therapy was initiated according to the national guidelines for non-neutropenic patients, in the form of intravenous fluconazole (10 mg/kg twice daily as a loading dose for the first day, and subsequently 10 mg/kg once daily as a maintenance dose) or classical amphotericin B (0.5 1 mg/kg intravenously as a single dose per day) as the first choice before culture results were available. If Aspergillus was identified, treatment was switched to voriconazole (6 mg/kg twice daily for the first day as a loading dose, and subsequently 4 mg/ kg once daily as a maintenance dose). If renal or liver function test abnormalities, or allergic reactions, were detected, or culture results were obtained, caspofungin (70 mg per day intravenously as a loading dose, and a maintenance dose of 50 mg/day) or liposomal amphotericin B (5 mg/kg intravenously as a single dose per day) were substituted. In the case of patients with plaque formation, the duration of treatment was 4 8 weeks, depending on observations of changes in the plaques. When there was no plaque formation, the duration of treatment was 2 4 weeks, and in those patients with candidaemia the duration of treatment was 14 days, or until the final blood culture was negative for fungi. Statistical analysis Descriptive analyses were used for the evaluation of the data, with SPSS statistical software (SPSS version 15.0; SPSS, Chicago, IL, USA). Data were expressed as median, interquartile range (25 75%), and percentage (%), where appropriate. The Mann Whitney U-test was used for non-parametric data, and the chi-square test was used for dichotomous variables. A p-value of <0.05 was assumed to be significant. Results During the study period, 634 patients were admitted to our respiratory ICU, and 246 underwent bronchoscopy for various reasons. TBFI was suspected in 95 patients (case group), and the other 151 patients were accepted as the control group. The demographic data and ICU outcomes of all of the study subjects are summarized in Table 1. Both groups were similar with respect to demographics, comorbidities, APACHE II score on admission to the ICU, and mortality rates. However, the case group had a higher rate and longer duration of invasive mechanical ventilation than the control group. The length of stay in the ICU was significantly greater in the case group. Fungal cultures of BAL fluids were positive in 74 patients (30.1%). In the case group (n = 95), 63 patients (66.3%) had a positive fungal culture; in the control group (n = 151), 11 patients (7.3%) had a positive fungal culture. The sensitivity, specificity and positive and negative predictive values of the bronchoscopic view of TBFI as compared with BAL fluid results were as follows: 85.1% (63/74), 81.4% (140/172), 66.3% (63/95), and 92.7% (140/151), respectively. Among the 95 case patients, the microbiology results of 63 (66.3%) revealed fungi (90.5% Candida species; 9.5% Aspergillus). Biopsies were performed in 78 patients; the other 17 patients refused the biopsy. Bronchoscopy was performed in 32 of the 95 case patients via the nasal route, and eight of these patients had plaque formations on the vocal cords. Four of these cases were intubated after bronchoscopy, as they were unresponsive to non-invasive mechanical ventilation. The remaining patients had bronchoscopy via an endotracheal tube. Histopathology revealed fungi in 28 (35.9%) patients; 50 (64.1%) showed no fungi. Patients defined as TBFI proven, probable, possible, colonization and no TBFI according to the bronchoscopic view, BAL fluid culture and histopathology are summarized in Fig. 2. Bronchoscopy was performed in the first 3 days of ICU admission in the majority of patients (73.3%). The median time to bronchoscopy in the ICU was 2 days (interquartile range:

4 CMI Yazıcıoglu Mocßin et al. Bronchoscopy as an indicator of TBFI E139 TABLE 1. Patient group demographics and intensive-care unit (ICU) data of patients with suspected tracheobronchial fungal infection (TBFI) Suspected TBFI: case No TBFI suspected: control p-value Number of patients Demographic data Age in years (range) 66 (56 72) 66 (56 76) 0.46 Gender, male/female 70/25 98/ Comorbidities, n (%) COPD 63 (66.3) 94 (62.3) 0.52 Diabetes 18 (18.9) 22 (14.6) 0.37 Cancer 12 (12.6) 19 (12.6) 0.99 ICU data APACHE II score (range) 22 (17 27) 22 (17 26) 0.83 Reason for ARF, n (%) Pneumonia 35 (36.8) 57 (37.7) 0.93 COPD exacerbation 58 (61.1) 89 (58.9) Cardiogenic oedema 1 (1.1) 2 (2.0) Restrictive lung disease 1 (1.1) 2 (1.3) Mechanical ventilation IMV, n (%) 63 (66.3) 79 (52.3) IMV (days) (range) 8 (3 15) 4 (2 9) NIMV, n (%) 65 (68.4) 109 (72.2) 0.53 NIMV (days) (range) 8 (4 10) 5 (2 10) 0.07 Tracheostomy, n (%) 21 (22.1) 25 (16.6) 0.28 Length of ICU stay in days (range) 11 (7 20) 8 (4 14) ICU mortality, n (%) 22 (23.2) 39 (25.8) 0.64 ARF, acute respiratory failure; COPD, chronic pulmonary obstructive disease; IMV, invasive mechanical ventilation; NIMV, non-invasive mechanical ventilation. 1 4). Plaques were mostly seen at the tracheal mucosa next to the vocal cords, at the distal part of the trachea, or at the bilateral bronchial mucosa. Table 2 shows the relationship between plaque formation and the laboratory data. In the case group, empirical antifungal treatment was given in 82 cases after observing typical TBFI, on the basis of the patient s clinical results. Antifungal treatment for suspected TBFI, before any microbiology and histopathology results had been acquired, was given to 26 of 28 proven TBFI patients, 31 of 42 probable TBFI patients, and 25 of 25 of possible TBFI patients. In the control group, no patient received empirical antifungal treatment. Two patients whose histology and BAL culture results were positive for fungi did not receive antifungal therapy, as these patients died before the decision to initiate therapy could be made. Renal supplement dialysis was not required for any of the patients while they were in the ICU. Mortality rates in the ICU in the proven, probable and possible TBFI cases were 28.6% (8/28), 21.4% (9/42), and 24.0% (6/25), respectively. In the control group, the mortality rates in the ICU for patients with colonization and no TBFI were 45.5% (5/11) and 24.3% (34/140), respectively. None of the patients who died underwent an autopsy. Discussion In this study, we showed that endobronchial inflammatory lesions detected by FB revealed that the majority of mucosal plaques were related to invasive fungal disease in critically ill, non-neutropenic patients. Although bacterial infections significantly contribute to mortality in the ICU, fungal diseases are increasingly being seen in non-neutropenic, critical patients [17,18]. In the EPIC-II study, which evaluated the prevalence and outcomes of infections in the ICU, fungal isolates constituted 21% of all positive blood cultures [19]. In another study, as many as 5.5% of the ICU patients, in the absence of neutropenia, had a confirmed Candida infection [4]. Previously, several authors have also reported the occurrence of invasive pulmonary aspergillosis in COPD patients, with a very high mortality rate [20 24]. On the whole, data related to TBFI in non-neutropenic patients hospitalized in the ICU are lacking. In the present study, histopathology showed yeast-like pseudohyphae among the necrotic cells and the surface epithelium, acute inflammatory cell infiltration, and fibrin in the bronchial and tracheal mucosa. Blood vessel invasion by fungi was not found in any of our cases. In a review that evaluated the distribution of fungal species in TBFI, Aspergillus species (53%) and Coccidioides Bronchoscopy in the Respiratory ICU, N = 246 Bronchoscopy findings such as: Whitish,sticky secretions, oedematous hyperaemic mucosa, and/or mucosal plaque formation on vocal cords or/and epiglottis or/and upper or lower part of tracheal mucosa No TBFI N = 151 Suspected TBFI N = 95 Absent Present N = 151 Pathology for fungi N = 78 N = 17 ( ) N = 140 (+) N = 11 Fungi present N = 28 Fungi absent N = 50 BAL(+) N = 12 BAL( ) N = 5 FIG. 2. The results of suspected tracheobronchial fungal infection (TBFI) by bronchoscopy. ICU, intensive-care unit. No TBFI Colonization BAL (+) N = 28 BAL (+) N = 30 BAL ( ) N = 20 Proven TBFI N = 28 Probable TBFI N = 42 Possible TBFI N = 25

5 E140 Clinical Microbiology and Infection, Volume 19 Number 3, March 2013 CMI TABLE 2. The relationship of plaque development and the laboratory data of 95 patients with suspected tracheobronchial fungal infection (TBFI) Variables Plaque (+), n = 56 Plaque ( ), n = 39 p-value Fungi, n (%) (BAL fluids) Candida albicans 4 (7.1) 5 (12.8) 0.09 Candida non-albicans 25 (44.6) 17 (43.5) Aspergillus spp. 6 (10.7) 0 Candida albicans + non-albicans 3 (5.4) 0 Isolation of pathogenic bacteria from BAL fluid, n (%) Pseudomonas aeruginosa 10 (17.8) 7 (17.9) 0.30 Methicillin-resistant Staphylococcus 11(19.6) 4 (10.3) aureus Klebsiella pneumonia 5 (8.9) 4 (10.3) Enterococci 18 (1.7) 1(2.7) Acinetobacter baumannii 13 (23.2) 2 (5.1) Escherichia coli 3 (5.4) 1(2.7) Other enteric bacteria 2 (3.6) 3(7.8) Isolation of multiple bacteria (>2) 32 (57.1) 18 (46.1) 0.29 Histopathology for fungi (+), n (%) 26/48 (54) 2/30 (6.7) BAL, bronchoalveolar lavage. immitis (16%) were reported to be the most frequent. The patients in this review were mostly immunocompromised, and the percentage of Candida was very low (6%) [12]. In contrast, in our study, the Candida isolates were responsible for 90.5% of all TBFIs, whereas Aspergillus species were responsible for only 9.5%. We were unable to subclassify the Candida isolates, because of inadequate laboratory resources. When whitish plaques were detected on bronchoscopic examination, TBFI was confirmed histopathologically in more than half of the cases. Consequently, the detection of whitish plaques by FB should alert the treating clinician to the presence of an invasive fungal disease, according to our data. In a prospective and post-mortem study performed in critically ill and non-neutropenic patients, various factors, such as antibiotic use, duration of antibiotic treatment, mechanical ventilation period, age, acute respiratory distress syndrome, parenteral nutrition, and gender, did not affect Candida isolation from the lungs [25]. According to our data, antifungal treatment is strictly indicated when whitish tracheobronchial plaques are detected on bronchoscopic examination, as TBFI was confirmed histopathologically in a couple of days in more than half (54%) of the cases. In this study, TBFIs caused by non-albicans types of Candida constituted three-quarters of all biopsy-proven Candida infections. Non-albicans Candida species are known to have higher resistance to fluconazole [26 28]. The treating clinician should also bear in mind that an early start of rational antifungals in invasive fungal disease has a profound impact on mortality [6,29]. In the present study, we did not have antifungal susceptibility test results. Meersseman et al. [30] showed that, in 77 pneumonia patients in whom tracheal lavage revealed Candida, no Candida could be histologically detected post-mortem. No autopsies were performed on our patients, and fungal pneumonia was not evaluated with lung biopsy. Wood et al. [31] performed a study in a level 1 trauma ICU, where they included 62 patients whose BAL fluid was positive for Candida. They suggested that isolation of Candida from BAL fluid in quantities below the diagnostic threshold for ventilator-associated pneumonia in this population does not require antifungal therapy. However, we treated the majority of patients who were biopsy-negative, because their clinical severity and bronchoscopic appearance were identical to those of histologically proven cases. Delisle et al. performed a study to investigate Candida colonization and its associated risk factors, and to examine the clinical outcomes, in patients with clinical suspicion of ventilator-associated pneumonia with concordant Candida colonization (n = 114) and without Candida colonization (n = 525) [32]. They stated that it is unclear whether Candida colonization is causally related to poor outcome, or whether it is a marker for increased morbidity and mortality in the ICU. The mortality rate in our patients with Candida colonization was greater than in the respiratory tract Candida colonization group of Delisle et al. (45.5% vs. 32.4%), and they also did not treat these patients with antifungal drugs. The mortality rate of patients with no TBFI was nearly similar to that of the TBFI cases (proven, probable, and possible), and lower than that of the Candida colonization group. The length of ICU stay in the study of Delisle et al. was nearly seven times higher than in our study (59.9 vs. 8 days). Kontoyiannis et al. performed a study to evaluate the BAL results for diagnosis of fungal infections [33]. Our study showed the BAL results for diagnosis of TBFI were similar according to sensitivity and negative predictive values (85.1%, 92.7% versus 85%, 93%, respectively) and higher in specificity and positive predictive value when compared to the study done by Kontoyiannis et al. (81.4%, 66.3% versus 60%, 42% respectively) [33]. There are some limitations to our study. First, we could not subclassify Candida species and perform antifungal susceptibility tests, owing to inadequate laboratory resources. Moreover, we did not perform post-mortem biopsies to further determine the exact cause of death and to assess Candida invasion in other tissues. Our data are from patients with ARF, the majority of whom had chronic obstructive pulmonary disease and used inhaler steroids, and for this reason our TBFI rates might be higher, and our results should not be generalized for all patients. In conclusion, in our study, cases of suspected TBFI following a specific bronchoscopic view were nearly always verified by a positive fungal culture in the tracheobronchial lavage fluids. In the presence of plaque in the airway mucosa, the chance of a positive pathology finding for fungi appears to be increased. Our results might be helpful to intensivists

6 CMI Yazıcıoglu Mocßin et al. Bronchoscopy as an indicator of TBFI E141 attempting to diagnose and treat colonization or infection with fungi in patients with ARF in the ICU when BAL fluids are positive for fungi. Thus, ICU patients, particularly those with ARF, appear to have a greater chance of developing TBFI, which can be easily detected by bronchoscopic examination. If tracheobronchial plaques are detected by bronchoscopy, a definite diagnostic approach and empirical therapy for fungi should be seriously considered. Transparency Declaration All authors declare no dual or conflicting interest. References 1. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (suppl 2): American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: Samarakoon P, Soubani AO. Invasive pulmonary aspergillosis in patients with COPD: a report of five cases and systematic review of the literature. Chron Respir Dis 2008; 5: Leon C, Alvarez-Lerma F, Ruiz-Santana S et al. Fungal colonization and/or infection in non-neutropenic critically ill patients: results of the EPCAN observational study. Eur J Clin Microbiol Infect Dis 2009; 28: Azoulay E, Cohen Y, Zahar JR et al. Practices in non-neutropenic ICU patients with Candida-positive airway specimens. Intensive Care Med 2004; 30: Ruping MJ, Vehreschild JJ, Cornely OA. Patients at high risk of invasive fungal infections: when and how to treat. Drugs. 2008; 68: Xie GH, Fang XM, Fang Q et al. Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients. Crit Care 2008; 12: R5. 8. Martin SJ, Cohen PR, MacFarlane DF, Grossman ME. Cutaneous manifestations of Strongyloides stercoralis hyperinfection in an HIVseropositive patient. Skinmed 2011; 9: Pabuccuoglu U, Tuncer C, Sengiz S. Histopathology of candidal hyperplastic lesions of the larynx. Pathol Res Pract 2002; 198: Lipsker D, Chosidow O. White lesions of the oral mucosa. Rev Prat 2002; 52: Bodey GP. Fungal infections in the cancer patient. S Afr Med J 1977; 52: Karnak D, Avery RK, Gildea TR, Sahoo D, Mehta AC. Endobronchial fungal disease: an under-recognized entity. Respiration 2007; 74: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Apache II: a severity of disease classification system. Crit Care Med 1985; 13: De Pauw B, Walsh TJ, Donnelly JP et al. European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008; 46: Luna M, Candidiasis. In: Connor DH, Chandler FW, Schwartz DA, Manz HS, Lack EE, eds, Pathology of infectious diseases. Hong Kong, Stanford: Application & Large G, 1997; Morace G, Borghi E. Fungal infections in ICU patients: epidemiology and the role of diagnostics. Minerva Anestesiol 2010; 76: Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through N Engl J Med 2003; 348: Vincent JL, Rello J, Marshall J et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302: Ader F, Nseir S, Le Berre R et al. Invasive pulmonary aspergillosis in chronic obstructive pulmonary disease: an emerging fungal pathogen. Clin Microbiol Infect 2005; 11: Bulpa PA, Dive AM, Garrino MG et al. Chronic obstructive pulmonary disease patients with invasive pulmonary aspergillosis: benefits of intensive care? Intensive Care Med 2001; 27: Rello J, Esandi ME, Mariscal D, Gallego M, Domingo C, Valles J. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: report of eight cases and review. Clin Infect Dis 1998; 26: Dimopoulos G, Piagnerelli M, Berre J, Eddafali B, Salmon I, Vincent JL. Disseminated aspergillosis in intensive care unit patients: an autopsy study. J Chemother 2003; 15: Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004; 170: el-ebiary M, Torres A, Fabregas N et al. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients An immediate postmortem histologic study. Am J Respir Crit Care Med. 1997; 156: Nguyen MH, Peacock JE, Jr, Morris AJ et al. The changing face of candidemia: emergence of non-candida albicans species and antifungal resistance. Am J Med 1996; 100: Pfaller MA, Jones RN, Messer SA, Edmond MB, Wenzel RP. National surveillance of nosocomial blood stream infection due to species of Candida other than Candida albicans: frequency of occurrence and antifungal susceptibility in the SCOPE program. SCOPE participant group. Surveillance and Control of Pathogens of Epidemiologic. Diagn Microbiol Infect Dis. 1998; 30: Pfaller MA, Messer SA, Gee S et al. In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents. J Clin Microbiol 1999; 37: Mulanovich VE, Kontoyiannis DP. Fungal pneumonia in patients with hematologic malignancies: current approach and management. Curr Opin Infect Dis 2011; 24: Meersseman W, Lagrou K, Spriet I et al. Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med 2009; 35: Wood GC, Mueller EW, Croce MA, Boucher BA, Fabian TC. Candida sp. isolated from bronchoalveolar lavage: clinical significance in critically ill trauma patients. Intensive Care Med 2006; 32: Delisle MS, Williamson DR, Perreault MM, Albert M, Jiang X, Heyland DK. The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients. J Crit Care 2008; 23: Kontoyiannis DP, Reddy BT, Torres HA et al. Pulmonary candidiasis in patients with cancer: an autopsy study. Clin Infect Dis 2002; 34: